Efficacy and Safety of Neoadjuvant Olaparib Monotherapy and Olaparib Plus Durvalumab Combination in HER2-Negative BRCAm Breast Cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 Oct 2022 → 17 Sep 2025

Decision date (initial)

2024-09-29

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca AB

External identifiers

EU CT number

2023-503529-20-00

EudraCT number

2021-005231-22

ClinicalTrials.gov

NCT05498155

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Efficacy, Therapy, Safety, Pharmacokinetic

To evaluate the efficacy, measured by pCR rate, of olaparib monotherapy and olaparib plusdurvalumab combination therapy, as assessed by central pathology review.

Secondary objectives 1

1. To evaluate the efficacy, measured by pCR rate, of olaparib monotherapy and olaparib plus durvalumab combination therapy as assessed by local pathology review -To evaluate the efficacy, measured by RCB, of olaparib monotherapy and olaparib plus durvalumab combination therapy as assessed by central pathology review -To evaluate the efficacy, measured by RCB, of olaparib monotherapy and olaparib plus durvalumab combination therapy as assessed by local pathology review -To evaluate the efficacy of olaparib monotherapy and olaparib plus durvalumab combination therapy in terms of change from baseline tumour volume -To evaluate the efficacy of olaparib monotherapy and olaparib plus durvalumab combination therapy by assessment of EFS -To assess the safety and tolerability profile of olaparib monotherapy and olaparib plus durvalumab combination therapy -To assess the safety and tolerability profile of olaparib monotherapy when given as adjuvant therapy to participants who achieve pCR

Conditions and MedDRA coding

BRCA Mutations and Early Stage HER2-Negative Breast Cancer

Study design 6 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. Males or Females ≥18 years - Minimum body weight of 30 kg - Capable of giving signed informed consent. - Male and Female participants of childbearing potential must use effective methods ofcontraception - Histologically confirmed, newly diagnosed, primary, operable, non-metastatic invasivebreast cancer with the following characteristics: --ER-negative or ER-low defined as IHC nuclear staining ≤10% - HER2-negative (not eligible for anti-HER2 therapy) defined as: -- IHC 0, 1+ without in situ hybridization OR -- In situ hybridization non-amplified with ratio less than 2.0 OR -- In situ hybridization average HER2 copy number < 6 signals/cells - Clinical TNM staging (per AJCC 8th Edition) as follows: -- T1b (>5 mm but ≤10 mm), N0, no known metastases (M0 or MX); OR -- T1c (>10 mm but ≤20 mm), N0, no known metastases (M0 or MX); OR -- T1 (>1 mm but ≤20 mm), N1, no known metastases (M0 or MX); OR -- T2 (>20 mm but ≤50 mm), N0, no known metastases (M0 or MX).). - Documented deleterious or suspected deleterious mutation in BRCA1 or BRCA2 from localBRCA testing using either a germline or tumour test. - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Participants must have adequate organ and bone marrow function - Participant must be willing to undergo a baseline research core needle biopsy prior to startof study treatment. - Participant must be willing to have any leftover tumour tissue/FFPE from the diagnosticbiopsy submitted for research purposes, if available. For a complete overview of the inclusion criteria refer to the protocol.

Exclusion criteria 1

1. Any evidence of other diseases (such as severe or uncontrolled systemic diseases or active, uncontrolled infections, including but not limited to, uncontrolled ventricular arrhythmia, uncontrolled hypertension, recent [within 3 months] myocardial infarction, uncontrolled major seizure disorder, renal transplant, active bleeding diseases, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography scan - Refractory nausea and vomiting, chronic gastrointestinal disease likely to interfere with absorption of the study medication, inability to swallow the formulated product - History of another primary malignancy except for malignancy treated with curative intent with no known active disease for ≥5 years before the first dose of study intervention and of low potential risk for recurrence - Participants with MDS or AML - For higher risk (Cohort B) participants only: Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, sarcoidosis, granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc), autoimmune pneumonitis, and autoimmune myocarditis - Known active hepatitis infection, positive hepatitis C antibody, hepatitis B virus surface antigen or hepatitis B virus core antibody - Known to have tested positive for human immunodeficiency virus unless currently on effective anti-retroviral therapy with an undetectable viral load within 6 months - History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (Common Terminology Criteria for Adverse Events [CTCAE] Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia - Participant must not have had any prior treatment for the current breast cancer, including surgery, chemotherapy, hormonal therapy, radiation, or experimental therapy - For higher risk (Cohort B) participants only: Prior exposure to anti-PD1, anti-PD-L1, or anti-CTLA4 agents (ICIs); OR an agent directed to other co-inhibitory or co-stimulatory T-cell receptors - Any concurrent anticancer treatment - Major surgical procedure (excluding placement of vascular access, local surgery of isolated lesions, or diagnostic staging) within 2 weeks of the first dose of study intervention - For higher risk (Cohort B) participants only: Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. - Concomitant use of: -- Known strong cytochrome P450 (CYP3A) inhibitors or moderate CYP3A inhibitors within 2 weeks prior to first dose of study intervention -- Known strong CYP3A inducers or moderate CYP3A inducers .The required washout period prior to starting study therapy is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents For a complete overview of the exclusion criteria refer to the protocol.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. pCR is defined as ypT0/Tis ypN0 (ie, no invasive residual in breast and the axillary lymph nodes on evaluation of the complete resected breast specimen and all sampled regional lymph nodes) following completion of neoadjuvant systemic therapy

Secondary endpoints 5

1. pCR is defined as ypT0/Tis ypN0 (ie, no invasive residual in breast and the axillary lymph nodes on evaluation of the complete resected breast specimen and all sampled regional lymph nodes) following completion of neoadjuvant systemic therapy.
2. RCB index value using 6 variables to categorize response in 1 of 4 classes: RCB 0 (pCR), I (minimal RCB), II (moderate RCB), and III (extensive RCB).
3. Percentage change in tumour volume from baseline after 3 and 6 cycles of treatment will be measured using MRI.
4. EFS is defined as time from the first dose of study intervention administration to any of the following events: progression of disease that precludes surgery, local or distant recurrence after surgery, second primary malignancy (breast or other invasive cancers), or death due to any cause.
5. Safety and tolerability will be evaluated in terms of AEs/SAEs, physical examination, vital signs including blood pressure, pulse, heart rate, body temperature, body weight and height, clinical laboratory assessments including clinical chemistry/haematology parameters, and ECGs.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

Astraallen Gartuna, Karlebyhus Byggnad 674 Karlebyhus Byggnad 674

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Public contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Third parties 1

Locations

5 EU/EEA countries · 26 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 35 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications